Evaluation of Urea-Based Inhibitors of the Dopamine Transporter Using the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

Md Ashraf-Uz-Zaman, Guangchen Ji, Dalton Tidwell, Linda Yin, Smathorn Thakolwiboon, Jie Pan, Riley Junell, Zach Griffin, Sadisna Shahi, Derek Barthels, Md Sanaullah Sajib, Paul C. Trippier, Constantinos M. Mikelis, Hiranmoy Das, Mirla Avila, Volker Neugebauer, Nadezhda A. German

Research output: Contribution to journalArticlepeer-review

Abstract

The dopaminergic system is involved in the regulation of immune responses in various homeostatic and disease conditions. For conditions such as Parkinson’s disease and multiple sclerosis (MS), pharmacological modulation of dopamine (DA) system activity is thought to have therapeutic relevance, providing the basis for using dopaminergic agents as a treatment of relevant states. In particular, it was proposed that restoration of DA levels may inhibit neuroinflammation. We have recently reported a new class of dopamine transporter (DAT) inhibitors with high selectivity to the DAT over other G-protein coupled receptors tested. Here, we continue their evaluation as monoamine transporter inhibitors. Furthermore, we show that the urea-like DAT inhibitor (compound 5) has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors in the experimental autoimmune encephalomyelitis model mimicking clinical signs of MS. To the best of our knowledge, this is the first study reporting the beneficial effects of DAT inhibitor-based treatment in animals with induced autoimmune encephalomyelitis, and the observed results provide additional support to the model of DA-related neuroinflammation.

Original languageEnglish (US)
Pages (from-to)217-228
Number of pages12
JournalACS Chemical Neuroscience
Volume13
Issue number2
DOIs
StatePublished - Jan 19 2022

Keywords

  • dopamine
  • dopamine transporter inhibitor
  • modafinil
  • multiple sclerosis
  • neuroinflammation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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